Zolinza (Vorinostat) - Description and Clinical Pharmacology

DESCRIPTION

ZOLINZA contains vorinostat, which is described chemically as N- hydroxy- N'- phenyloctanediamide.

The empirical formula is C₁₄H₂₀N₂O₃. The molecular weight is 264.32 and the structural formula is:

Vorinostat is a white to light orange powder. It is very slightly soluble in water, slightly soluble in ethanol, isopropanol and acetone, freely soluble in dimethyl sulfoxide and insoluble in methylene chloride. It has no chiral centers and is non-hygroscopic. The differential scanning calorimetry ranged from 161.7 (endotherm) to 163.9°C. The pH of saturated water solutions of vorinostat drug substance was 6.6. The pKa of vorinostat was determined to be 9.2.

Each 100 mg ZOLINZA capsule for oral administration contains 100 mg vorinostat and the following inactive ingredients: microcrystalline cellulose, sodium croscarmellose and magnesium stearate. The capsule shell excipients are titanium dioxide, gelatin and sodium lauryl sulfate.

CLINICAL PHARMACOLOGY

Mechanism Of Action

Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations (IC₅₀<86 nM). These enzymes catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. In some cancer cells, there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones. Hypoacetylation of histones is associated with a condensed chromatin structure and repression of gene transcription. Inhibition of HDAC activity allows for the accumulation of acetyl groups on the histone lysine residues resulting in an open chromatin structure and transcriptional activation. In vitro, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells. The mechanism of the antineoplastic effect of vorinostat has not been fully characterized.

Pharmacokinetics

Absorption

The pharmacokinetics of vorinostat were evaluated in 23 patients with relapsed or refractory advanced cancer. After oral administration of a single 400-mg dose of vorinostat with a high-fat meal, the mean ± standard deviation area under the curve (AUC) and peak serum concentration (C_max) and the median (range) time to maximum concentration (T_max) were 5.5±1.8 µM●hr, 1.2±0.62 µM and 4 (2-10) hours, respectively.

In the fasted state, oral administration of a single 400-mg dose of vorinostat resulted in a mean AUC and C_max and median T_max of 4.2±1.9 µM●hr and 1.2±0.35 µM and 1.5 (0.5-10) hours, respectively. Therefore, oral administration of vorinostat with a high-fat meal resulted in an increase (33%) in the extent of absorption and a modest decrease in the rate of absorption (T_max delayed 2.5 hours) compared to the fasted state. However, these small effects are not expected to be clinically meaningful. In clinical trials of patients with CTCL, vorinostat was taken with food.

At steady state in the fed-state, oral administration of multiple 400-mg doses of vorinostat resulted in a mean AUC and C_max and a median T_max of 6.0±2.0 µM●hr, 1.2±0.53 µM and 4 (0.5-14) hours, respectively.

Distribution

Vorinostat is approximately 71% bound to human plasma proteins over the range of concentrations of 0.5 to 50 µg/mL.

Metabolism

The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by β-oxidation. Human serum levels of two metabolites, O -glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. Compared to vorinostat, the mean steady state serum exposures in humans of the O -glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, respectively.

In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP).

Excretion

Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of vorinostat. The mean urinary recovery of two pharmacologically inactive metabolites at steady state was 16±5.8% of vorinostat dose as the O‑ glucuronide of vorinostat, and 36±8.6% of vorinostat dose as 4-anilino-4-oxobutanoic acid. Total urinary recovery of vorinostat and these two metabolites averaged 52±13.3% of vorinostat dose. The mean terminal half-life (t_½) was ~2.0 hours for both vorinostat and the O -glucuronide metabolite, while that of the 4-anilino-4-oxobutanoic acid metabolite was 11 hours.

Special Populations

Based upon an exploratory analysis of limited data, gender, race and age do not appear to have meaningful effects on the pharmacokinetics of vorinostat.

Pediatric

Vorinostat was not evaluated in patients <18 years of age.

Hepatic Insufficiency

Vorinostat was not evaluated in patients with hepatic impairment. [See Use in Specific Populations.]

Renal Insufficiency

Vorinostat was not evaluated in patients with renal impairment. However, renal excretion does not play a role in the elimination of vorinostat. [See Use in Specific Populations.]

Pharmacokinetic effects of vorinostat with other agents

Vorinostat is not an inhibitor of CYP drug metabolizing enzymes in human liver microsomes at steady state C_max of the 400 mg dose (C_max of 1.2 µM vs IC₅₀ of >75 µM). Gene expression studies in human hepatocytes detected some potential for suppression of CYP2C9 and CYP3A4 activities by vorinostat at concentrations higher (≥10 µM) than pharmacologically relevant. Thus, vorinostat is not expected to affect the pharmacokinetics of other agents. As vorinostat is not eliminated via the CYP pathways, it is anticipated that vorinostat will not be subject to drug-drug interactions when co-administered with drugs that are known CYP inhibitors or inducers. However, no formal clinical studies have been conducted to evaluate drug interactions with vorinostat.

In vitro studies indicate that vorinostat is not a substrate of human P-glycoprotein (P-gp). In addition, vorinostat has no inhibitory effect on human P-gp-mediated transport of vinblastine (a marker P-gp substrate) at concentrations of up to 100 μM. Thus, vorinostat is not likely to inhibit P-gp at the pharmacologically relevant serum concentration of 2 μM (C_max) in humans.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been performed with vorinostat.

Vorinostat was mutagenic in vitro in the bacterial reverse mutation assays (Ames test), caused chromosomal aberrations in vitro in Chinese hamster ovary (CHO) cells and increased the incidence of micro-nucleated erythrocytes when administered to mice (Mouse Micronucleus Assay).

Effects on the female reproductive system were identified in the oral fertility study when females were dosed for 14 days prior to mating through gestational day 7. Doses of 15, 50 and 150 mg/kg/day to rats resulted in approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC. Dose dependent increases in corpora lutea were noted at ≥15 mg/kg/day, which resulted in increased peri-implantation losses were noted at ≥50 mg/kg/day. At 150 mg/kg/day, there were increases in the incidences of dead fetuses and in resorptions.

No effects on reproductive performance were observed in male rats dosed (20, 50, 150 mg/kg/day; approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC), for 70 days prior to mating with untreated females. [See Warnings and Precautions.]

CLINICAL STUDIES

Cutaneous T-cell Lymphoma

In two open-label clinical studies, patients with refractory CTCL have been evaluated to determine their response rate to oral ZOLINZA. One study was a single-arm clinical study and the other assessed several dosing regimens. In both studies, patients were treated until disease progression or intolerable toxicity.

Study 1

In an open-label, single‑arm, multicenter non-randomized study, 74 patients with advanced CTCL were treated with ZOLINZA at a dose of 400 mg once daily. The primary endpoint was response rate to oral ZOLINZA in the treatment of skin disease in patients with advanced CTCL (Stage IIB and higher) who had progressive, persistent, or recurrent disease on or following two systemic therapies. Enrolled patients should have received, been intolerant to or not a candidate for bexarotene. Extent of skin disease was quantitatively assessed by investigators using a modified Severity Weighted Assessment Tool (SWAT). The investigator measured the percentage total body surface area (%TBSA) involvement separately for patches, plaques, and tumors within 12 body regions using the patient’s palm as a “ruler”. The total %TBSA for each lesion type was multiplied by a severity weighting factor (1=patch, 2=plaque and 4=tumor) and summed to derive the SWAT score. Efficacy was measured as either a Complete Clinical Response (CCR) defined as no evidence of disease, or Partial Response (PR) defined as a ≥50% decrease in SWAT skin assessment score compared to baseline. Both CCR and PR had to be maintained for at least 4 weeks.

Secondary efficacy endpoints included response duration, time to progression, and time to objective response.

The population had been exposed to a median of three prior therapies (range 1 to 12).

Table 2 summarizes the demographic and disease characteristics of the Study 1 population.

Table 2 Baseline Patient Characteristics (All Patients As Treated)

	Vorinostat
Characteristics	(N=74)
Age (year)
Mean (SD)	61.2 (11.3)
Median (Range)	60.0 (39.0, 83.0)
Gender, n (%)
Male	38 (51.4%)
Female	36 (48.6%)
CTCL stage, n (%)
IB	11 (14.9%)
IIA	2 (2.7%)
IIB	19 (25.7%)
III	22 (29.7%)
IVA	16 (21.6%)
IVB	4 (5.4%)
Racial Origin, n (%)
Asian	1 (1.4%)
Black	11 (14.9%)
Other	1 (1.4%)
White	61 (82.4%)
Time from Initial CTCL Diagnosis (year)
Median (Range)	2.6 (0.0, 27.3)
Clinical Characteristics
Number of prior systemic treatments, median (range)	3.0 (1.0, 12.0)

The overall objective response rate was 29.7% (22/74, 95% CI [19.7 to 41.5%]) in all patients treated with ZOLINZA. In patients with Stage IIB and higher CTCL, the overall objective response rate was 29.5% (18/61). One patient with Stage IIB CTCL achieved a CCR. Median times to response were 55 and 56 days (range 28 to 171 days), respectively in the overall population and in patients with Stage IIB and higher CTCL. However, in rare cases it took up to 6 months for patients to achieve an objective response to ZOLINZA.

The median response duration was not reached since the majority of responses continued at the time of analysis, but was estimated to exceed 6 months for both the overall population and in patients with Stage IIB and higher CTCL. When end of response was defined as a 50% increase in SWAT score from the nadir, the estimated median response duration was 168 days and the median time to tumor progression was 202 days.

Using a 25% increase in SWAT score from the nadir as criterion for tumor progression, the estimated median time-to-progression was 148 days for the overall population and 169 days in the 61 patients with Stage IIB and higher CTCL.

Response to any previous systemic therapy does not appear to be predictive of response to ZOLINZA.

Study 2

In an open-label, non-randomized study, ZOLINZA was evaluated to determine the response rate for patients with CTCL who were refractory or intolerant to at least one treatment. In this study, 33 patients were assigned to one of 3 cohorts: Cohort 1, 400 mg once daily; Cohort 2, 300 mg twice daily 3 days/week; or Cohort 3, 300 mg twice daily for 14 days followed by a 7-day rest (induction). In Cohort 3, if at least a partial response was not observed then patients were dosed with a maintenance regimen of 200 mg twice daily. The primary efficacy endpoint, objective response, was measured by the 7‑point Physician’s Global Assessment (PGA) scale. The investigator assessed improvement or worsening in overall disease compared to baseline based on overall clinical impression. Index and non-index cutaneous lesions as well as cutaneous tumors, lymph nodes and all other disease manifestations were also assessed and included in the overall clinical impression. CCR required 100% clearing of all findings, and PR required at least 50% improvement in disease findings.

The median age was 67.0 years (range 26.0 to 82.0). Fifty-five percent of patients were male, and 45% of patients were female. Fifteen percent of patients had Stage IA, IB, or IIA CTCL and 85% of patients had Stage IIB, III, IVA, or IVB CTCL. The median number of prior systemic therapies was 4 (range 0.0 to 11.0).

In all patients treated, the objective response was 24.2% (8/33) in the overall population, 25% (7/28) in patients with Stage IIB or higher disease and 36.4% (4/11) in patients with Sezary syndrome. The overall response rates were 30.8%, 9.1% and 33.3% in Cohort 1, Cohort 2 and Cohort 3, respectively. The 300 mg twice daily regimen had higher toxicity with no additional clinical benefit over the 400 mg once daily regimen. No CCR was observed.

Among the 8 patients who responded to study treatment, the median time to response was 83.5 days (range 25 to 153 days). The median response duration was 106 days (range 66 to 136 days). Median time to progression was 211.5 days (range 94 to 255 days).